Pathologic changes in the small airways represent the key element in the pathogenesis of chronic obstructive pulmonary disease (COPD), as they precede the development of emphysema and contribute to progressive irreversible airflow obstruction, the hallmark of COPD. However, specific molecular mechanisms and cellular origin of COPD-associated small airway disorder in humans remain largely unknown. Based on the knowledge from murine studies that signaling via fibroblast growth factor receptor (FGFR) 2 in distal airway epithelial progenitors is critical for the establishment of distal lung epithelial architecture and branching morphogenesis during lung development, and our preliminary evidence that FGFR2 pathway is down-regulated in the small airway epithelium (SAE) of smokers and smokers with COPD in association with suppression of the key molecular features of the distal lung phenotype, and that FGFR2 is expressed in basal cells (BC), the stem/progenitor cells of the airway epithelium, where it is suppressed by smoking and smoking-associated epidermal growth factor (EGF) and transforming growth factor (TGF)-beta, the central hypothesis of this project is that smoking-dependent suppression of FGFR2 signaling in SAE BC stem/progenitor cells of COPD smokers renders these cells less potent in generating normally differentiated SAE and less capable of maintaining small airway integrity via SAE repair and regeneration. Capitalized on our recently developed methodology to isolate BC from the human SAE and characterize stem/progenitor functions of these cells in vitro, the goal of this project is to test this central hypothesis by addressing the following Specific Aims: Aim 1. T evaluate the hypothesis that BC from the SAE of COPD smokers have reduced capacity to generate normally differentiated SAE and regenerate SAE after injury but, instead, produce an altered SAE phenotype similar to that present in the SAE of COPD smokers in vivo. Aim 2. To test the hypothesis that FGFR2 signaling is important for human SAE BC function relevant to differentiation and maintenance of the adult human SAE and that suppression of SAE BC FGFR2 by smoking-related factors will result in an altered SAE BC phenotype similar to that exhibited by SAE BC of COPD smokers as defined in Aim 1. Aim 3. To assess the hypothesis that normalization of FGFR2 signaling in SAE BC of COPD smokers by lentiviral vector-mediated FGFR2 overexpression, application of FGFR2-activating signals and suppression of smoking-induced EGF and TGF-beta pathways will restore the capacity of these cells to generate and maintain normally differentiated SAE. If proven correct, restoration of FGFR2 signaling in SAE BC of COPD smokers could be a novel therapeutic approach to prevent progression of COPD-associated small airway disorder at the earliest stages.